Inherited Genetic Variation in Parkinson's Disease: Convergence on Impaired Autophagosome-Lysosome Fusion Through the Altered Expression of mRNA Isoforms.

Parkinson's disease (PD) pathogenesis involves complex interactions between genetic factors. We employed two-sample Mendelian randomization (MR) integrating tissue-specific gene regulatory networks to identify causal genes and regulatory elements modulating PD risk. Two-sample MR analysis identified 79 putative causal genes for PD. A subset of the 79 causal genes was enriched within chr17q21.31 and chr16p11.2 cytobands that have been previously linked to neurodevelopmental disorders. Functional enrichment analysis of the 79 genes revealed autophagosome-lysosome fusion as a key process. Ten genes (ELOVL7, HSD3B7, PLEKHM1, PRSS53, SNCA, STX1B, STX4, ZSWIM7, LINC02210, and RP11-1072 A3.3) showed causal associations with tissue-specific expression patterns driving risk or protection for PD. Further investigation into their tissue-specific isoform expression profile revealed isoform-specific contributions to disease risk (or protection). These findings highlight the critical role of isoform-specific expression of causal genes in modulating PD risk, particularly relating to autophagosome-lysosome fusion. While our findings provide new insights into PD susceptibility, we acknowledge that the observed isoform-specific changes may, in part, reflect sample selection bias. Therefore, further experimental verification is needed to confirm the importance of incorporating tissue-specific gene isoform profiles in understanding PD causal mechanisms.